A comparative genomic approach, which began with the analysis of the unusual slo-2 gene in C. elegans has led to the molecular identification of the long sought-after mammalian Na+-activated potassium channel (KNa). KNa channels have been identified in cardiomyocytes and neurons where they may serve as an important protective mechanism against ischemia (Dryer, 1994). Our studies showed that the C. elegans gene, slo-2, also confers resistance to hypoxia (Yuan et al, submitted). Our studies further showed that mammalian KNa channels are encoded by the rSlack gene (Joiner, et al, 1998) (rslo2), a mammalian orthologue of the C. elegans slo-2 gene. We showed that rSLO-2 channels have all the properties of native KNa channels. We now plan to follow up on these findings by investigating the role of SLO-2 channels in different classes of identified neurons (in C. elegans), cloning and functionally characterizing two distinct mammalian slo-2 genes present in human (and mouse) genomes, and defining the structural regions in mammalian SLO-2 channels which are responsible for the salient property of sensing Na + and CI-. In addition to extending our theoretical understanding of the factors involved in ion channel activation, this information may be important for clinical applications. Pharmacological agents which modulate the KNa channel, especially channel openers, might serve a useful role in preventing cell damage during cardiac ischemia and stroke, and may serve as a protective agent in the pretreatment of organs used in transplant procedures.